Process for producing carbostyril derivatives

ABSTRACT

The present invention provides a process for producing carbostyril derivatives (I) which are known to be useful as medical drug such as antithrombotic agent, cerebral circulation improver, anti-inflammatory agent, antiulcer agent, etc. in a high yield and a high purity. The carbostyril derivatives (I) can be produced by reacting a carbostyril derivative (II) with a tetrazole derivative (III) in the presence of a phase transfer catalyst.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of pending U.S. application Ser. No.10/208,738, filed Aug. 1, 2002, which is a continuation-in-partapplication of U.S. application Ser. No. 09/869,264 filed Jun. 27, 2001,abandoned, the disclosures of which are incorporated herein byreference.

TECHNICAL FIELD

The present invention relates to a novel process for producingcarbostyril derivatives, and more particularly to a novel process forproducing carbostyril derivatives represented by the following generalformula (I):

wherein A represents a lower alkylene group; R represents a cycloalkylgroup; and the bond between the 3- and 4-positions of the carbostyrilskeleton represents a single bond or a double bond.

BACKGROUND ART

The compound represented by the above-mentioned general formula (I),namely the objective compound of the present invention, is known to beuseful as an antithrombotic agent, a cerebral circulation improver, ananti-inflammatory agent, an antiulcer agent, a hypotensive agent, anantiasthmatic agent, and a phosphodiesterase inhibitor, etc. (see:JP-A-56-49378 and U.S. Pat. No. 4,277,479).

The carbostyril derivatives represented by the general formula (I) haveso far been produced by reacting a carbostyril derivative represented bythe following general formula (II):

wherein the bond between the 3- and 4-positions of the carbostyrilskeleton is as defined above, with a tetrazole derivative represented bythe following general formula (III′):

wherein X′ represents a halogen atom, and A and R are as defined above,in the presence of an inorganic base or an organic base (see:JP-A-56-49378; U.S. Pat. No. 4,277,479; and Chem. Pharm. Bull., 31(4),1151-1157 (1983)).

DISCLOSURE OF THE INVENTION

According to the above-mentioned known process, the yield of thecompound of general formula (I) is as low as about 50 to 74%, becausethere is also formed a compound in which the tetrazole derivative ofgeneral formula (III′) has reacted not only with the hydroxyl group ofthe carbostyril derivative of general formula (II) but also with the1-position of the carbostyril derivative of general formula (I)simultaneously. Since the thus formed contaminative impurity isdifficult to remove, production of a compound of general formula (I)having a high purity has required a complicated process of purification.

It is an object of the present invention to provide a process forproducing a carbostyril derivative represented by the general formula(I) at a low cost and by a simple procedure. It is another object of thepresent invention to provide a process for producing a carbostyrilderivative represented by the general formula (I) without anycomplicated process of purification, in a high yield, and in a highpurity. It is yet another object of the present invention to provide anindustrially advantageous process for producing the carbostyrilderivatives represented by the general formula (I).

Further, on the basis of the growing conscious to internationalenvironmental conservation in recent years, great demands become arisenin a chemical industry to make every effort decreasing use of thesolvents and reagents pointed out the harmfulness, and preventing thosematerials from discharging into the environment. In order to fulfilthose demands, established processes have to be down for aconsideration, alternative raw materials, reagents and solvents beingless harmful have to be found out, and the processes having higherconversion rate, yield and selectivity have to be developed; so that theenvironmental load can be diminished. Under the circumstances with thesesocial demands, it is further object of the present invention to providea process being safe for the environment, for producing a carbostyrilderivative represented by the general formula (I) with using phasetransfer catalyst in water.

In view of the above-mentioned present situation, the present inventorshave conducted various studies with the aim of achieving theabove-mentioned objects. As a result, it has been found in the processof the studies surprisingly that, when a phase-transfer catalyst is usedas a catalyst, a compound of general formula (I) given by a reactionbetween the hydroxyl group of the carbostyril derivative of generalformula (II) and the tetrazole derivative of general formula (III′) isformed, and a compound given by the reaction between the 1-position ofthe carbostyril derivative of general formula (I) and the tetrazolederivative of general formula (III′) is scarcely formed, and thereaction progresses position-specifically, and thereby the objects ofthe present invention can be achieved. Based on this finding, thepresent invention has been accomplished.

According to the present invention, the objective carbostyril derivativerepresented by the general formula (I) can be obtained in a high yieldand a high purity by reacting a carbostyril derivative represented bythe following general formula (II):

wherein the bond between the 3- and 4-positions of the carbostyrilskeleton represents a single bond or a double bond, with a tetrazolederivative represented by the following general formula (III):

wherein X represents a halogen atom or a group causing the samesubstitution reaction as that caused by halogen atom, A represents alower alkylene group, and R represents a cycloalkyl group, in thepresence of a phase-transfer catalyst.

According to the process of the present invention, the hydroxyl group ofthe carbostyril derivative of general formula (II) and the tetrazolederivative of the general formula (III) can be made to react selectivelyand thereby the objective carbostyril derivative of general formula (I)can be produced on an industrial scale, at a low cost, by a simpleprocedure, in a high yield and in a high purity.

BEST MODE FOR CARRYING OUT THE INVENTION

As examples of the lower alkylene group represented by A in the generalformulas (I) and (III) of this specification, mention can be made of,straight chain or branched chain alkylene groups having 1-6 carbon atomssuch as methylene, ethylene, propylene, tetramethylene, 2-ethylethylene,pentamethylene, hexamethylene, 2-methyltrimethylene,2,2-dimethyl-trimethylene, 1-methyltrimethylene and the like. Amongthese lower alkylene groups, particularly preferred is tetramethylenegroup.

As the cycloalkyl group represented by R in the general formulas (I) and(III), mention can be made of, for example, cycloalkyl groups having 3-8carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl and the like. Among these cycloalkyl groups,particularly preferred is cyclohexyl group.

As the halogen atom represented by X in the general formula (III),mention can be made of fluorine atom, chlorine atom, bromine atom andiodine atom, among which particularly preferred is chlorine atom.

As specific examples of the group causing the same substitution reactionas that caused by the halogen atom represented by X in the compound ofgeneral formula (III), mention can be made of lower alkanesulfonyloxygroup, arylsulfonyloxy group, aralkylsulfonyloxy group and the like. Asspecific examples of the lower alkanesulfonyloxy group, mention can bemade of methanesulfonyloxy, ethanesulfonyloxy, isopropanesulfonyloxy,propanesulfonyloxy, butanesulfonyloxy, tert-butanesulfonyloxy,pentanesulfonyloxy, hexanesulfonyloxy and the like. As specific examplesof the arylsulfonyloxy group, mention can be made of substituted orunsubstituted arylsulfonyloxy groups such as phenylsulfonyloxy,4-methylphenylsulfonyloxy, 2-methylphenylsulfonyloxy,4-nitrophenylsulfonyloxy, 4-methoxyphenylsulfonyloxy,3-chlorophenylsulfonyloxy, α-naphthylsulfonyloxy and the like. Asspecific examples of the aralkylsulfonyloxy group, mention can be madeof substituted or unsubstituted aralkylsulfonyloxy groups such asbenzylsulfonyloxy, 2-phenylethylsulfonyloxy, 4-phenylbutylsulfonyloxy,4-methylbenzylsulfonyloxy, 2-methylbenzylsulfonyloxy,4-nitrobenzylsulonyloxy, 4-methoxybenzylsulfonyloxy,3-chlorobenzylsulfonyloxy, α-naphthylmethylsuflonyloxy and the like.Among the groups represented by X, particularly preferred are halogenatoms.

As the bond between the 3- and 4-positions of the carbostyril skeletonin the general formulas (I) and (II), a single bond is particularlypreferred.

Next, the process of the present invention will be explained in moredetail with reference to reaction schemes.

wherein X, A, R and the bond between the 3- and 4-positions of thecarbostyril skeleton are as defined above.

In the reaction Scheme-1, the reaction between a compound of generalformula (II) and a compound of general formula (III) is carried out inan appropriate solvent in the presence of a phase-transfer catalyst andfurther a basic compound. As the solvent used herein, all the inertsolvents can be used so far as they exercise no adverse influence on thereaction. Examples of the solvent usable include water; alcohols such asmethanol, ethanol, propanol, isopropyl alcohol, butanol, ethylene glycoland the like; ethers such as dimethyl ether, diethyl ether, diisopropylether, t-butyl methyl ether, tetrahydrofuran, dioxane, monoglyme,diglyme and the like; ketones such as acetone, methyl ethyl ketone,ethyl isobutyl ketone and the like; aromatic hydrocarbons such asbenzene, o-dichlorobenzene, chlorobenzene, toluene, xylene and the like;esters such as methyl acetate, ethyl acetate, butyl acetate and thelike; aprotic polar solvents such as N,N-dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide and the like; and mixtures thereof.Among these solvents, particularly preferred are mixtures of water andan aromatic hydrocarbon such as benzene, o-dichlorobenzene,chlorobenzene, toluene, xylene and the like, and water itself alone.

As the basic compound, known ones can be used extensively. Examplesthereof include inorganic bases such as sodium hydroxide, potassiumhydroxide, cesium hydroxide, lithium hydroxide, sodium carbonate,potassium carbonate, cesium carbonate, lithium carbonate, lithiumhydrogen carbonate, sodium hydrogen carbonate, potassium hydrogencarbonate, silver carbonate and the like; alkali metals such as sodium,potassium and the like; alcoholates such as sodium methylate, sodiumethylate and the like; metallic salts of organic acids such as sodiumacetate and the like; and organic bases such as triethylamine,diisopropylethylamine, pyridine, N,N-dimethylaniline,N-methyl-morpholine, 4-dimethylaminopyridine,1,5-diazabicyclo-[4.3.0]non-5-ene (DBN),1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane(DABCO) and the like; and mixtures thereof. Among these bases, inorganicbases such as potassium carbonate, cesium carbonate, lithium carbonate,lithium hydroxide, lithium hydrogen carbonate, sodium hydroxide,potassium hydroxide, potassium hydrogen carbonate, sodium carbonate,sodium hydrogen carbonate, and the like; and mixtures thereof areparticularly preferred.

As the phase transfer catalyst, mentioned can be made of, for example,quaternary ammonium salts substituted with a residue selected from thegroup consisting of straight or branched chain alkyl group having 1-18carbon atoms, phenyl lower alkyl group including a straight or branchedchain alkyl group having 1 to 6 carbon atoms which is substituted by aphenyl group and phenyl group, such as tetrabutylammonium chloride,tetrabutylammonium bromide, tetrabutylammonium fluoride,tetrabutylammonium iodide, tetrabutylammonium hydroxide,tetrabutylammonium hydrogen sulfate, tributylmethylammonium chloride,tributylbenzylammonium chloride, tetrapentylammonium chloride,tetrapentylammonium bromide, tetrahexylammonium chloride,benzyldimethyloctylammonium chloride, methyltrihexylammonium chloride,benzylmethyloctadecanylammonium chloride, methyltridecanylammoniumchloride, benzyltripropylammonium chloride, benzyltriethylammoniumchloride, phenyltriethylammonium chloride, tetraethylammonium chloride,tetramethylammonium chloride and the like; phosphonium salts substitutedwith a residue selected from the group consisting of straight orbranched chain alkyl groups having 1-18 carbon atoms such astetrabutylphosphonium chloride and the like; and pyridinium saltssubstituted with a straight or branched chain alkyl group having 1-18carbon atoms such as 1-dodecanylpyridinium chloride and the like. Amongthese phase transfer catalysts, quaternary ammonium salts substitutedwith a straight or branched chain alkyl group having 1-18 carbon atomssuch as tetrabutylammonium chloride and the like are particularlypreferred. As the salt-forming ions in these salts, hydroxyl ion,hydrogen sulfate ion and halogen ions are preferred, among whichchlorine ion is particularly preferred. If desired, sodium sulfite orthe like may be added to the reaction system of the above-mentionedreaction for the purpose of preventing the coloration caused byoxidation.

The reaction is carried out usually at a temperature not lower thanambient temperature and not higher than 200° C., and preferably at atemperature of 50-150° C. The reaction time is usually from about onehour to about 10 hours. It is recommended to use the compound (III)usually in an amount of at least 0.5 mol, preferably 0.5-1.5 mol per molof the compound (II) and more preferably 1.1 to 1.5 mol per mol of thecompound (II), to use the basic compound usually in an amount of 1-5 molper mol of the compound (II), and to use the phase transfer catalystusually in an amount of 0.1-1 mol and preferably 0.1-0.5 mol per mol ofthe compound (II).

The reaction may be carried out with circulating the reaction mixture bycontinuous disperser. The reaction mixture is repeatedly introduced intothe continuous disperser and pulverized therein, then returned to thereaction vessel so as to circulate the reaction mixture constantly. Thecirculation of the reaction mixture can prevent the crystals of theobjective product represented by the formula (I) from adhering with eachother to make big agglomerates.

The compound of general formula (I) obtained by the above-mentionedreaction can easily be isolated by the conventional separating means. Assaid separating means, mention can be made of, for example, extractionmethod using a solvent, dilution method, recrystallization method,column chromatography, preparative thin layer chromatography, etc.

EXAMPLES

Next, the process of the present invention is more concretely explainedbelow with reference to examples. The invention is by no means limitedthereby.

Example 1

Into a three-necked flask having a capacity of 300 ml were introduced10.00 g of 6-hydroxy-3,4-dihydrocarbostyril, 16.36 g of1-cyclohexyl-5-(4-chlorobutyl)-1,2,3,4-tetrazole, 10.16 g of potassiumcarbonate, 3.00 g of tetrabutylammonium chloride, 0.05 g of sodiumsulfite, 30 ml of toluene and 50 ml of water. The content of the flaskwas heated under reflux for 8 hours with stirring. After cooling thereaction mixture to ambient temperature, the deposited crystallineproduct was collected by filtration and washed with 50 ml of water.Then, the crude crystal thus obtained was introduced into 70 ml of 90%methanol cooled to 5° C., and stirred at 5° C. for 10 minutes for thesake of washing. The crystal was collected by filtration and furtherwashed on the suction filter with 20 ml of 90% methanol cooled to 5° C.The crystal was dried to obtain 21.46 g (yield 95%) of6-[4-(1-cyclohexyl-1,2,3,4-tetrazol-5-yl)butoxy]-3,4-dihydrocarbostyrilas a colorless needle-like crystalline product.

Purity: 99.80%; m.p.: 158-159° C.

The purity was measured by high performance liquid chromatography underthe following conditions:

-   -   Column: YMC Pack SIL A-002 (manufactured by YMC Co.)    -   Moving phase: dichloromethane/n-hexane/methanol=20/10/1    -   Detector: UV, 254 nm    -   Flow rate: 0.90 ml/min.    -   Retention time: 4.7 min.

Example 2

Into a flask having a capacity of 200 ml were introduced 12.00 g of6-hydroxy-3,4-dihydrocarbostyril, 19.60 g of1-cyclohexyl-5-(4-chlorobutyl)-1,2,3,4-tetrazole, 8.20 g of 50% aqueoussolution of tetrabutylammonium chloride, 12.20 g of potassium carbonate,0.60 g of sodium sulfite and 60 ml of water. The content of the flaskwas heated under reflux for 8 hours with stirring. After the reaction,the reaction mixture was cooled to ambient temperature, and thedeposited crude crystal was once collected by filtration. After washingthe crystal firstly with 36 ml of methanol and then with 60 ml of water,the crystal was again introduced into a flask having a capacity of 200ml and heated under reflux together with 84 ml of methanol for 2 hours.The solution thus obtained was cooled to 10° C. The crystal wascollected by filtration, washed firstly with 24 ml of methanol and thenwith 24 ml of water, and dried at 80° C. Thus, 23.84 g (yield 87.7%) of6-[4-(1-cyclohexyl-1,2,3,4-tetrazol-5-yl)butoxy]-3,4-dihydrocarbostyrilwas obtained as a colorless needle-like crystalline product.

Purity: 99.89%; m.p.: 158-159° C.

The purity was measured by high performance liquid chromatography (HPLC)under the same conditions as in Example 1.

Example 3

Into a reaction vessel having a capacity of 100 L were introduced 5 kgof 6-hydroxy-3,4-dihydrocarbostyril (30.64 mol), 8.2 kg of1-cyclohexyl-5-(4-chlorobutyl)-1,2,3,4-tetrazole (33.78 mol), 4.7 kg ofpotassium carbonate (34.01 mol), 1.0 kg of sodium hydroxide (25 mol),3.5 kg of 50% aqueous solution of tetrabutylammonium chloride (6.30mol), 0.25 kg of sodium sulfite (1.98 mol), and 25 L of water. Themixture of the reactants was heated at 85° C. (80˜90° C.) for 6 hourswith circulating by continuous disperser (pipeline homomixer PL-SLmanufactured by TOKUSHUKIKA KOGYO CO. LTD.). After the completion of thereaction, the reaction mixture was cooled to around 50° C. and 15 L ofmethanol were added thereinto. The reaction mixture with methanol washeated under reflux for 30 minutes. The obtained reaction mixture wascooled to 10 to 20° C. for 30 minutes or more, and the crystals wereseparated out. The obtained crystals were washed with 25 L of water, 15L of methanol, and 25 L of water in this order, then dried at 80° C. forabout 10 hours. Thus, 10.87 kg (yield: 95.95%) of6-[4-(1-cyclohexyl-1,2,3,4-tertazol-5-yl)butoxy]-3,4-dihydrocarbostyrilwas obtained as colorless needle-like crystal.

Purity: 99.71%; m.p.: 158-159° C.

The purity was measured by high performance liquid chromatography (HPLC)under the same conditions as in Example 1.

Example 4

Into a flask having a capacity of 500 ml were introduced 30 g of6-hydroxy-3,4-dihydrocarbostyril (0.18 mol), 49.09 g of1-cyclohexyl-5-(4-chlorobutyl)-1,2,3,4-tetrazole (0.20 mol), 101.63 g ofpotassium carbonate (0.74 mol), 1.5 g of sodium sulfite (0.01 mol),20.43 g of 50% aqueous solution of tetrabutylammonium chloride (0.04mol), and 150 ml of water. The mixture of the reactants was heated atabout 85° C. (80 to 90° C.) for 6 hours with circulating by continuousdisperser (pipeline homomixer T.K. ROBO MIX manufactured by TOKUSHUKIKAKOGYO CO. LTD.). After the completion of the reaction, the reactionmixture was cooled to around 20° C., and the precipitated crystallineproduct was collected by filtration and washed with 150 ml of water (5times volume). The obtained crystalline product was introduced into aflask having a capacity of 1 L, and washed with 600 ml of water understirring at about 90° C. for about 1 hour. The solution thus obtainedwas cooled, and the crystal was collected by filtration and washed with150 ml of water (5 times volume), then dried at about 80° C. for 10hours. Thus, 67.40 g (yield: 99.23%) of6-[4-(1-cyclohexyl-1,2,3,4-tertazol-5-yl)butoxy]-3,4-dihydrocarbostyrilwas obtained.

Then, 60 g of the crystal obtained and 90 ml of methanol were introducedinto a flask having a capacity of 1 L, and the crystal was washed withstirring at about 25° C. for about 10 minutes. After cooling themixture, the crystal was collected by filtration and washed with 45 mlof methanol. The crystal obtained was dried at about 80° C. for 10 hoursto obtain 58.18 g (yield: 96.97%) of6-[4-(1-cyclohexyl-1,2,3,4-tertazol-5-yl)butoxy]-3,4-dihydrocarbostyrilas colorless needle-like crystal.

Purity: 99.73%; m.p.: 158-159° C.

The total yield of the objective6-[4-(1-cyclohexyl-1,2,3,4-tertazol-5-yl)butoxy]-3,4-dihydrocarbostyrilwas 96.22%. The purity was measured by high performance liquidchromatography (HPLC) under the same conditions as in Example 1.

1. A process for preparing cilostazol comprising: a) dissolving6-hydroxy-3,4-dihydroquinolinone and a water-soluble base in water toform an aqueous phase, b) dissolving a1-cyclohexyl-5-(4-halobutyl)tetrazole in a water-immiscible solvent toform an organic phase, c) forming a biphasic mixture by contacting theaqueous phase and the organic phase in the presence of a quaternaryammonium phase transfer catalyst, d) and recovering cilostazol from thebiphasic mixture.
 2. The process of claim 1 wherein the molar quantityof the 6-hydroxy-3,4-dihydroquinolinone is greater than the molarquantity of the l-cyclohexyl-5-(4-halobutyl)tetrazole.
 3. The process ofclaim 1 wherein the water-immiscible solvent is selected from the groupconsisting of toluene, hexane, dichloromethane and mixtures thereof. 4.The process of claim 1 wherein the quaternary ammonium phase transfercatalyst is selected from the group consisting oftricaprylylmethylammonium chloride, tetra-n-butylammonium bromide,benzyltriethylammonium chloride, cetyltrimethylammonium bromide,cetylpyridinium bromide, N-benzylquininium chloride,tetra-n-butylammonium chloride, tetra-n-butylammonium hydroxide,tetra-n-butylammonium iodide, tetra-ethylammonium chloride,benzyltributylammonium bromide, benzyltriethylammonium bromide,hexadecyltriethylammonium chloride, tetramethylammonium chloride,hexadecyltrimethyl ammonium chloride, and octyltrimethylammoniumchloride.
 5. The process of claim 4 wherein the quaternary ammoniumphase transfer catalyst is selected from the group consisting oftricaprylylmethyl ammonium chloride, tetrabutylammonium bromide,triethylbenzylammonium bromide and mixtures thereof.
 6. The process ofclaim 5 wherein the quaternary ammonium phase transfer catalyst istricaprylylmethyl ammonium chloride.
 7. The process of claim 1 whereinthe water-soluble base is an alkali metal hydroxide, carbonate orbicarbonate.
 8. The process of claim 7 wherein the water-soluble base isselected from the group consisting of NaOH, KOH, K₂CO₃, Na₂CO₃ andNaHCO₃.
 9. The process of claim 8 wherein the water-soluble base isNaOH.
 10. The process of claim 1 further comprising dissolving areaction promoter selected from the group consisting of potassiumcarbonate and sodium sulfate in the water.
 11. The process of claim 1wherein the 1-cyclohexyl-5-(4-halobutyl)-tetrazole is1-cyclohexyl-5-(4-chlorobutyl)tetrazole.
 12. Substantially purecilostazol prepared by the process of claim
 1. 13. A process forpurifying cilostazol by recrystallization from a solvent selected fromthe group consisting of 1-butanol, acetone, toluene, methyl ethylketone, dichloromethane, ethyl acetate, methyl t-butyl ether, dimethylacetamide-water mixtures, THF, methanol, isopropanol, benzyl alcohol,2-pyrrolidone, acetonitrile, Cellosolve, monoglyme, isobutyl acetate,sec-butanol, tert-butanol, DMF, chloroform, diethyl ether and mixturesthereof.
 14. Highly pure cilostazol free of impurities.
 15. Micronizedcilostazol of small particle size and narrow particle size distribution.16. Cilostazol having an average particle size of less than 200micrometer.
 17. Cilostazol having an average particle size of less than20 micrometer.